The formation and maintenance of the vertebrate skeleton requires the interactions of many cell types and growth factors and other molecules. The past decade has witnessed an explosive growth in the general understanding of growth factors and other proteins that mediate the complex coordination of bone formation and bone resorption by these different cell types in skeletal modeling and remodeling (Popoff and Marks, Oral and Maxillofacial Clinics of North America 9:563-579 (1997)).
In general, the bone remodeling cycle involves a complex series of sequential steps that are highly regulated. The initial “activation” phase of bone  remodeling begins early in fetal life and is dependent on the effects of local and systemic growth factors on mesenchymal cells of the osteoblast lineage (Eriksen, Endocrinol. Rev. 7:379-408 (1986)). These cells interact with hematopoietic precursors to form osteoclasts in the “resorption” phase. This leads to the differentiation, migration and fusion of the large multinucleated osteoclasts. These cells attach to the mineralized bone surface and initiate resorption by the secretion of hydrogen ions and lysosomal enzymes. Osteoclastic resorption produces irregular scalloped cavities on bone surface. Once the osteoclasts have completed their work of bone removal, there is a “reversal” phase during which mononuclear cells, which may be of the macrophage lineage, are present on the bone surface. These cells further degrade collagen, deposit proteoglycans, and release growth factors that signal the initiation of the “formation” phase. During the final formation phase of the remodeling cycle, the cavity created by resorption can be completely filled in with successive layers of osteoblasts, which differentiate from their mesenchymal precursors and lay down a mineralizable matrix. (Raisz, Clin. Chem. 45:1353-1358 (1999)).
With bone disorders associated with decreased bone mass, osteoclastic resorption outweighs osteoblastic bone formation, resulting in bone loss. While treatments that stimulate bone formation would be beneficial in treating or preventing bone loss, current therapies are suboptimal (Canalis, J. Clin. Invest. 106:177-179 (2000); Raisz, J. Bone Min. Metab 17:79-89 (1999)).
An animal model useful in bone studies is the osteopetrosis (op) mutation in the rat. Osteopetrosis describes a group of congenital bone disorders that are characterized by a generalized increase in skeletal mass resulting from a primary defect in osteoclast-mediated bone resorption (Popoff and Schneider, Molec. Med. Today 2:349-358 (1996)). Numerous osteopetrotic mutations have been described in other species, including human and mouse. The bone that is formed as the skeleton develops and grows in animals with this mutation is not resorbed,  resulting in the failure to develop bone marrow cavities. The osteopetrotic mutations are pathogenetically heterogeneous since the point at which osteoclast development or activation is intercepted differs for each mutation (Popoff and Marks, Bone 17:437-445 (1995)). Although osteoclast hypofunction is universal among the osteopetrotic mutations, genetic abnormalities involving osteoblast development/function (i.e., bone formation), mineral homeostasis and the immune and endocrine systems have also been reported within this disorder (Seifert et al., Clin. Orthop. 294:23-33 (1993)).
To date, pharmaceutical approaches to managing osteoporosis or osteopetrosis are of limited effectiveness. Therefore, alternative therapies are needed to modulate bone cell differentiation and bone formation, and to treat bone disorders such as osteoporosis and osteopetrosis.